Secondary metabolites, which are produced by living organisms, in particular microorganisms, and the chemical variants derived therefrom are successfully used as active agents in medicine. Particularly for the control of infectious diseases, the use of secondary metabolites has proven effective. A large portion of the antibiotics used today were isolated from bacteria in the soil, the so-called actinomycetes. Due to the development of resistances against the respectively used drugs, there is a permanent demand of new antibiotic active agents with novel activity mechanisms. In spite of their excellent antibiotic and other pharmacological properties, for many secondary metabolites the use as a drug is at last unsuccessful because of the in most cases also very distinct toxic properties for man.
Antibiotics from the class of the lipopeptides, which are characterized by a linear or cyclic peptide portion or a combination of both, with naturally and/or non-naturally derivatized and/or non-derivatized amino acids, with which a saturated or unsaturated acyl residue is connected, which optionally may be interrupted by one or several phenyl or cycloalkyl groups or connected with such groups or interrupted by one or several oxygen or nitrogen atoms, have been found in the past as very effective against fungi and Gram-positive bacteria. For the majority of these compounds, however, toxic properties are also known.
The compound daptomycin belonging to the class of the A-21978C lipopeptides for instance damages the skeletal muscle (Oleson et al. 2000, Anti-microbial agents and chemotherapy, Vol. 44 No 11; 2948-2953), and a series of further lipopeptides, for instance lichenysin (Grangemard I. et al., Applied Biochemistry and Biotechnology, Volume 90, Number 3, 2001, pp. 199-210(12)), surfactin A (Hanka Symmank, Peter Franke, Wolfram Saenger and Frank Bernhard, Modification of biologically active peptides: production of a novel lipohexapeptide after engineering of Bacillus subtilis surfactin synthetase) FR131535 and echinocandin (Fujie A, Iwamoto T, Sato B, Muramatsu H, Kasahara C, Furuta T, Hori Y, Hino M, Hashimoto S., Bioorg Med Chem Lett. 2001 Feb. 12; 11(3):399-402. FR131535, a novel water-soluble-echinocandin-like lipopeptide: synthesis and biological properties), Fengycin (J. of Antibiotics 29 (1986) 888-901), iturin A (Aranda F J, Teruel J A, Ortiz A., Biochem Biophys Acta. 2005 Jul. 15; 1713(1):51-6. Further aspects on the hemolytic activity of the antibiotic lipopeptide iturin A), and lipopeptides (DE 19807972) similar to amphomycin and friulimicin act in a hemolytic manner.
An essential problem for the application of these lipopeptides as drugs is however the elimination of the toxicological properties without impairing the antibiotic activity of the substances. For the application of these substances as drugs, it is therefore necessary to find pharmaceutical compositions, which compared to the pure substance have improved pharmacological properties. It is known, for instance, that the hemolytic properties of a substance or of an ion are reduced in the presence of the serum albumin, and this is caused by the interaction with the serum albumin (“masking effect”) (Caffrey J M Jr, Smith H A, Schmitz J C, Merchant A, Frieden E.: Hemolysis of rabbit erythrocytes in the presence of copper ions. Inhibition by albumin and ceruloplasmin. Biol Trace Elem Res. 1990 Apr. 25; (1):11-9). This masking effect with the serum albumin causes however in many cases also the loss of the desired properties of molecules, and thus also of the antibiotic activity of lipopeptides as illustrated in example 1 of this invention.
It is known in the art to use cyclodextrins in pharmaceutical compositions. Due to their circular structure, cyclodextrins have a hydrophilic exterior and hydrophobic inner pocket. By enclosing in particular hydrophobic sections of the molecules, cyclodextrins can achieve a “molecular encapsulation” or “masking” of active agents, which are used for instance as a protective envelope of sensitive molecules in cosmetic and pharmaceutical formulations. Thereby, improved solubilities of substances, but also reduced toxicities, such as for instance a reduction of the hemolytic properties of molecules (J. Pharmacobiodyn. 1983 6(6): 408-14. Protective mechanism of beta cyclodextrin for the hemolysis induced with phenothiazine neuroleptics in vitro. Irie T, Sunada M, Otagiri M, Uekama K.) are obtained.